Gadolinium-HU-308-incorporated micelles

In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004–2013.
[updated ].


There are two subtypes of cannabinoid receptors in mammalian tissues: CB1 and CB2 (1, 2). CB1 is expressed abundantly in neuronal terminals in the central nervous system (CNS) and in some peripheral tissues to inhibit neurotransmitter release. CB1 is found predominately in the striatum, hippocampus, substantia nigra, globus pallidus, and cerebellum. CB2 is present mainly on immune cells in the blood and peripheral tissues (the spleen) to modulate cytokine release (3). However, CB2 has been found in the CNS tissues (neurons and glial cells) at very low levels (4). Both receptor subtypes are coupled through Gi/o proteins to inhibit adenylate cyclase and to modulate potassium and calcium channels. CB1 has been shown to be involved in analgesia, regulation of food intake, and control of movement in normal subjects (3). Alteration of CB1 function has been implicated in a number of human diseases such as depression, schizophrenia, and obesity (5-7). Upregulation of CB2 in the brain is associated with neuroinflammation in disorders such as Alzheimer’s disease, multiple sclerosis, encephalitis, and Down’s syndrome (8). CB2 is also involved in inflammation associated with pain, osteoporosis, cancer, and liver diseases (9). Gadolinium (Gd), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective in enhancing proton relaxation because of its high magnetic moment and water coordination (10, 11). Gd-Diethylenetriamine pentaacetic acid (Gd-DTPA) was the first intravenous magnetic resonance imaging (MRI) contrast agent used clinically, and a number of similar Gd chelates have been developed in an effort to further improve clinical use. However, these low molecular weight Gd chelates have short blood and tissue retention times, which limit their use as imaging agents in the vasculature and cancerous tissues. Various macromolecular Gd complexes have demonstrated superior contrast enhancement for MRI of the vasculature and carcinomas (12-14); however, these Gd complexes cannot proceed into further clinical development because of high tissue accumulation and slow excretion of toxic Gd ions. Furthermore, they are largely nonspecific. HU-308 is a potent selective CB2 agonist in vitro and in mice (15, 16). HU-308 and Gd-DTPA were incorporated into di-stearoyl-polyethylene glycol-phosphatidylethanolamine 2000 (DSPE-PEG2000) micelles (CB2R-targeted micelles) for MRI of vulnerable atherosclerotic plaques (17, 18).

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